The objective of this program is to identify a human Orexin-1 receptor antagonist which is suitable for development as a treatment for cocaine addiction. The role of the hypothalamic Orexin system in substance seeking and craving has been previously shown using immunohistochemistry to demonstrate activation of orexigenic neurons in the lateral hypothalamus when conditioned animals received cues for cocaine, morphine or food; in addition, when the reward seeking behavior was extinguished, it could be reinstated by administration of an Orexin agonist, and could be blocked by the selective Orexin-1 receptor (OX1R) antagonist SB-334867. To date there have been no selective OX1R antagonists taken forward into clinical studies due to poor pharmaceutical properties. We have identified potent antagonists of OX1R with up to 40- fold selectivity over OX2R. These are promising starting points for optimization with a structure-based drug discovery approach, guided by experimentally determined structures of ligand-receptor complexes. The primary goal of this project is to select a highly selective Orexin-1 receptor antagonist as a candidate drug fo clinical development to treat cocaine addiction. This goal will be achieved through optimization of selective OX1R antagonists already identified by Heptares, refining their potency, selectivity, and ADMET properties, demonstrating their efficacy in animal models of addiction, and progressing the most promising molecule through pre-clinical development. A subsidiary goal, should the primary be unattainable, is to select a highly selective Orexin-1 receptor antagonist as a candidate drug for clinical development to treat nicotine addiction. Aim 1 - To optimize the current lead series of OX1R selective antagonists for efficacy testing. This will include iterative optimization of lead molecules, crystallization of ligand-receptor complexes, measuring the affinity and kinetics of binding and functional inhibition, in vitro DMPK and in vivo DMPK characterization. Aim 2 - To evaluate the in vivo efficacy of compounds in animal models of addiction. Suitable models have been developed and demonstrated to be sensitive to the administration of Orexin-1 antagonists. This aim will validate that the optimized Orexin-1 antagonist(s), show target engagement in rat brain, and efficacy in rat models of cocaine (and nicotine) addiction. Aim 3 - To progress the drug candidate through pre-clinical development to a point where it is ready for clinical studies. Synthesis of the drug candidate will be scaled up, and it will be subjected to detailed formulation, DMPK and toxicology studies, enabling submission of an IND application.